Geranylgeranyl transferase type II inhibition prevents myeloma bone disease.
Geranylgeranyl transferase II (GGTase II) is an enzyme that plays a key role in the isoprenylation of proteins. 3-PEHPC, a novel GGTase II inhibitor, blocks bone resorption and induces myeloma cell apoptosis in vitro. Its effect on bone resorption and tumor growth in vivo is unknown. We investigated the effect of 3-PEHPC on tumor burden and bone disease in the 5T2MM model of multiple myeloma in vivo. 3-PEHPC significantly reduced osteoclast numbers and osteoclast surface. 3-PEHPC prevented the bone loss and the development of osteolytic bone lesions induced by 5T2MM myeloma cells. Treatment with 3-PEHPC also significantly reduced myeloma burden in bone. The magnitude of response was similar to that seen with the bisphosphonate, risedronate. These data show that targeting GGTase II with 3-PEHPC can prevent osteolytic bone disease and reduce tumor burden in vivo, and represents a novel approach to treating tumors that grow in bone.
Lawson
Michelle A
MA
Academic Unit of Bone Biology, University of Sheffield, School of Medicine and Biomedical Science, Beech Hill Road, Sheffield S10 2RX, UK.
Coulton
Les
L
Academic Unit of Bone Biology, University of Sheffield, School of Medicine and Biomedical Science, Beech Hill Road, Sheffield S10 2RX, UK.
Ebetino
Frank H
FH
Procter & Gamble Pharmaceuticals, Mason, OH, USA.
Vanderkerken
Karin
K
Department of Hematology and Immunology, Vrije Universiteit Brussels (VUB), Brussels, Belgium.
Croucher
Peter I
PI
Academic Unit of Bone Biology, University of Sheffield, School of Medicine and Biomedical Science, Beech Hill Road, Sheffield S10 2RX, UK. Electronic address: p.croucher@sheffield.ac.uk.
D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002452:Cell Count; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D010024:Osteoporosis / Q000201:enzymology / Q000517:prevention & control; D017368:Protein Prenylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D000068296:Risedronic Acid; D014166:Transferases / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects
C410028:2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D011725:Pyridines; C095279:Rab geranylgeranyl transferase beta-subunit; D014166:Transferases; D000068296:Risedronic Acid; D012968:Etidronic Acid